Lentiviruses are non-oncogenic retroviruses which cause chronic progressive neurological diseases with unusually long incubation periods. Visna virus in sheep and caprine-arthritis-encephalitis-virus (CAEV) in goats, are the prototypes of this group of viruses, which in addition to the progressive neurological disease cause chronic pneumonitis and arthritis. These viruses cause persistent infections in vivo, replicating at a slow but continuous rate; they have pathogenic potential in vitro causing syncytia and cell lysis and replicate at a rapid and highly productive level. It has recently been shown that visna virus and CAEV are related to the human-T-cell lymphotropic virus type III (HTLV-III), the presumptive agent of AIDS. HTLV-III and the lentiviruses are morphologically indistinguishable, share considerable nucleotide sequence homology and cause neurological disease. The ability of the lentiviruses to replicate to high titer in vitro suggests that they have a high level of gene expression. However, during persisting infection in vivo gene expression appears to be down regulated by multiple factors including viral genetic elements, a unique lentivirus induced interferon and the stage of differentiation of the target cell. The aim of this proposal is to study the mechanisms of gene regulation which cause restricted replication in vivo. In particular, the cis- and trans-acting regulatory elements in the LTRs of these viruses will be studied to determine their roles in both positive and negative regulation. The mechanism of induction of the lentivirus induced interferon will be studied to determine the lentivirus signal. The step in viral replication which is restricted by this unique interferon will be determined. Finally, the basis for latency of the lentiviruses in monocytes will be studied to determine the state at which virus replication is restricted and the role of cellular and viral elements in this restriction.